Pharmacology of Polycystic Kidney Disease Proteins
Abstract
Topic Area: Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in every 400 to 1000 births, representing the most common, potentially lethal, inheritable disorder that mostly affects the kidneys but also other organs. ADPKD causes fluid-filled sacs, so-called cysts, to accumulate in the kidneys, leading to gross kidney enlargement, relentless loss of normal renal tissues, and ultimately end-stage renal diseases that require dialysis or transplantation. Other symptoms include flank pain, blood in the urine, frequent bladder and kidney infection, kidney stones, and cardiovascular conditions such as hypertension and intracranial aneurysm. ADPKD is often diagnosed between the ages of 30 and 40 and needs lifelong care because there is currently no cure for ADPKD. Limited treatment options can only manage or alleviate symptoms to some degree. ADPKD is caused by defects in either of two proteins, PKD1 or PKD2, which function as a receptor and an ion channel, respectively. PKD1 and PKD2 reside at the cell surface where they detect stimuli outside the cell and trigger responses inside the cell accordingly. At present, it remains unclear what stimuli activate PKD1 and PKD2 and what happens next inside the cell once they are activated. Here, we propose to develop activators of PKD1 and PKD2 proteins to address these two fundamental questions. First, we will search for small chemical compounds that can activate PKD1 and PKD2. Small chemical compounds, such as painkiller aspirin, are the most common class of drugs used in medicine. Second, we will search for peptide activators of PKD1 and PKD2 proteins from cone snail venoms. Marine cone snails produce venoms that comprise of a diverse repertoire of peptides for prey capture and defense. These peptides have evolved over millions of years to act on receptors and ion channels like PKD1 and PKD2 to rapidly paralyze prey or to deter predators. One cone snail peptide, Prialt, is marketed for the treatment of intractable pain. Third, we will generate antibodies for PKD1 and PKD2 proteins. Antibodies are produced by our body during infection or vaccination and are best known for their ability to recognize and protect us against invading pathogens. Antibodies are also increasingly used to treat cancers and other diseases by specifically recognizing and remedying the molecules that exhibit abnormal activities in diseased conditions. Discovery of activators for PKD1 and PKD2 proteins is of both basic and translational significance. Such activators will not only help us understand how malfunctions of PKD1 and PKD2 proteins cause ADPKD, they will also serve as drug leads for the development of effectively therapeutic strategies for the treatment of ADPKD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710158
Entities
People
- Erhu Cao
Organizations
- United States Army
- University of Utah